Targeting of Mitogen-Activated Protein Kinases and Phosphatidylinositol 3 Kinase Inhibits Hepatocyte Growth Factor/Scatter Factor–Induced Angiogenesis

• DOI: 10.1161/01.cir.0000077501.19266.e5
• Publication Date: 2003-06-04T01:20:01Z
• Authors: Shiladitya Sengupta; Lynda A. Sellers; Rung-Chi Li; Ermanno Gherardi; Ganlin Zhao; Nicki Watson; Ram Sasisekharan; Tai-Ping D. Fan
• Keywords: Flavonoids; Male; 0301 basic medicine; 570; Mice, Inbred BALB C; Hepatocyte Growth Factor; Morpholines; Neovascularization, Physiologic; Androstadienes; Drug Combinations; Mice; 03 medical and health sciences; Chromones; Animals; Humans; Biological Assay; Collagen; Endothelium, Vascular; Laminin; Enzyme Inhibitors; Mitogen-Activated Protein Kinases; Cell Division; Cells, Cultured

Hepatocyte growth factor/scatter factor (HGF/SF) can sufficiently and independently induce pathophysiological angiogenesis. However, the treatment strategies have mostly been unsuccessful. The present study is first to evaluate possible targeting of downstream signals for inhibition HGF/SF-induced angiogenesis.In a multichannel scratch assay with human endothelial cells (ECs), HGF/SF induced strong prolonged activation MAPK cell proliferation that was inhibited by PD98059 LY294002/wortmannin, selective inhibitors PI3K signaling modules, respectively. Western blotting demonstrated temporal relation between two pathways. Chemical chemoinvasion ECs in vitro blocked neovascularization into polymer scaffold vivo, as quantified vessel counts clearance radioactive 133Xe.These data indicate MEK represent promising approach clinical management pathological conditions characterized overt